PTAB

IPR2018-01427

Eli Lilly Co v. Teva Pharmaceuticals Intl GmbH

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Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide and Methods of Using Same
  • Brief Description: The ’649 patent claims relate to isolated human or humanized anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibodies having a specified high binding affinity. The patent discloses their use for treating CGRP-related conditions such as migraine headaches.

3. Grounds for Unpatentability

Ground 1: Claims 1-9 are obvious over Tan (1995) in view of Wimalawansa (1996) and Queen (Patent 6,180,370).

  • Prior Art Relied Upon:
    • Tan 1995 (K.K.C. Tan et al., Clin. Sci. 89:565-573 (1995))
    • Wimalawansa (S.J. Wimalawansa, Endocrine Reviews 17(5):533-585 (1996))
    • Queen (Patent 6,180,370)
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of references taught or suggested every limitation of the challenged claims. Independent claim 1 recites an isolated human or humanized anti-CGRP antagonist antibody with a binding affinity (KD) to human α-CGRP of 50 nM or less, measured by surface plasmon resonance (SPR). Petitioner asserted that Tan 1995 disclosed a murine anti-CGRP antagonist antibody (MAb C4.19) that bound to human α-CGRP with a KD of 1.9 nM, demonstrating both in vitro and in vivo efficacy and thus providing an ideal starting point. Wimalawansa, a comprehensive review article, explicitly proposed that "humanized anti-CGRP monoclonal antibodies" should be explored as therapeutic agents for diseases linked to CGRP, including migraine. Finally, Queen taught the "gold standard" and routine techniques for humanizing a murine antibody (like Tan's) by grafting its complementarity-determining regions (CDRs) onto a human antibody scaffold (e.g., IgG), a process known to preserve or improve the original antibody's high binding affinity. Measuring this affinity via SPR at 37°C was presented as a conventional and standard method by 2005 for characterizing therapeutic antibodies.
    • Petitioner further argued that the limitations of dependent claims 2-9 were also rendered obvious. These limitations—such as binding to the C-terminus of CGRP (claims 2-3), being an IgG isotype (claim 4), comprising an Fc region (claim 5) with impaired effector function (claim 6), or being in a pharmaceutical composition for systemic administration (claims 8-9)—were all described as well-known, routine, and desirable features for therapeutic antibodies in the prior art, including in the cited references and as admitted in the ’649 patent's own specification.
    • Motivation to Combine: A person of ordinary skill in the art (POSA) would have been motivated to combine the references to develop a safe and effective treatment for chronic, CGRP-mediated conditions like migraine. Wimalawansa identified the therapeutic target and suggested humanized antibodies as the solution. Tan provided a specific, potent murine antibody against that target. A POSA would combine Tan's antibody with Queen's humanization technology to reduce the immunogenicity of the murine antibody, a critical step for creating a therapeutic intended for repeated administration in humans. The goal was to create a predictable, effective, and safe humanized antibody with high affinity, precisely what the challenged claims cover.
    • Expectation of Success: Petitioner asserted a POSA would have had a reasonable expectation of success. By 2005, creating murine monoclonal antibodies against a known antigen like CGRP was a well-established practice, as shown by Tan. Furthermore, humanization via CDR grafting as taught by Queen was a "clinically well-validated technology" known to successfully preserve the binding affinity and specificity of the donor antibody. The ’649 patent itself admitted that generating and humanizing antibodies, as well as measuring their affinity via SPR, involved "known," "established," and "conventional techniques." Therefore, a POSA would have reasonably expected to successfully produce a humanized anti-CGRP antibody meeting all the claimed criteria.
    • Key Aspects: Petitioner contended that the near-simultaneous, independent development of similar humanized anti-CGRP antibodies by at least two other entities (including Lilly itself) was strong objective evidence of obviousness. The petition also argued that the Patent Owner incorrectly asserted during prosecution that Tan "taught away" from using a full-length antibody, when Tan in fact demonstrated its in vivo activity and provided express guidance on how to improve its efficacy through repeated administration.

4. Key Claim Construction Positions

  • Petitioner asserted that, for the purposes of the proceeding, the terms “anti-CGRP antagonist antibody” and “humanized antibody” must be construed to encompass fragments thereof, such as Fab, Fab', and F(ab')2.
  • This construction was based on the express definitions provided within the ’649 patent's own specification. Petitioner argued this construction is critical because the prior art, particularly Tan, discloses data for both a full-length antibody and its Fab' fragment, both of which would fall within the scope of the claims under this construction.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325(d) would be inappropriate because the evidence submitted was not previously considered by the Office during prosecution.
  • Specifically, it was argued that the Examiner did not cite the primary references—Tan 1995, Wimalawansa, or Queen—in any Office Action. Petitioner noted that while these references were listed in an Information Disclosure Statement containing nearly 100 references, they were never substantively reviewed, and the Examiner did not have the benefit of the petitioner's arguments or expert declarations explaining their significance and combination.

6. Relief Requested

  • Petitioner requested that the Board institute an inter partes review, conduct a trial, and find claims 1-9 of the ’649 patent unpatentable as obvious.